Four research groups that incorporate drug design, synthetic, biological and mechanistic expertise are brought together in this proposal to pursue the development of anti-HIV-1 drugs that target a nucleic acid at some stage of progression in viral replication. The targets range from the viral RNA genome to intergrated proviral DNA. The four specific areas fo drug development in the proposal are: 1) Anti-rev Cations: Furan derivatives that are specific inhibitors of the critical rev-RRE protein-RNA interactions in the control of replication of HIV-1 have been discovered. New analogs will be prepared in efforts to increase specificity and affinity of the compounds for RRE while significantly decreasing binding to nonspecific sites. Biophysical studies on the nucleic acid complexes of the new compounds as well as model-based drug design studies will be conducted. 2) Threading Intercalators: Porphyrins, some of which bind to nucleic acids by threading intercalation, are some of the most active anti-HIV-1 derivatives discovered in a general anti-HIV-1 screen. Addintional threading interacalators, with peptide substituents that mimic tat and rev, will be developed to exploit these findings with porphyrins, and to determine what function the nucleic acid interactons play in their mechanism of action. The compounds will be designed to target viral sequencees such as RRE and TAR. 3) Triplex Targeting of Intergrated DNA: A difficult target for anti-HIV-1 drug action is the intergrated proviral DNA. A selective method of attack on this DNA involes triple-helix formation, but a limitation is the marginal stability of short nucleic acid triplexes. The investigators have designed a group of agents that cause dramatic increases in triple stability such that attack on intergrated DNA is feasible. They will continue to develop triplex specific compounds and will covalently link the best agents to oligonucleotides that target HIV-1 intergrated DNA to exploit the initial finds. 4) Novel rev and tat inhibitors: The investigators claim to have found that a DNA strand modified with N3'-->P5' phosphoramidates (NP) forms A-type duplexes that are more stable than with phosphodiesters. To exploit these findings an RRE hairpin will be synthesized with an NP strand to inhibit rev binding to the natural RRE. The NP A-type duplexes should compete with the viral RNA for rev (or tat and other proteins).